Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands
In view of the associated risks, it is important to limit treatment with vandetanib to patients who are in real need for treatment, i.e. with a symptomatic-aggressive course of the disease. Either symptomatic disease or progressive disease alone is not enough to prompt the need of treatment with vandetanib. Rate of change in biomarker levels such as of calcitonin (CTN) and/or carcinoembryonic antigen (CEA) as well as the rate of change of tumour volume during watchful waiting might help to identify not only patients in need for treatment but also the optimal moment to commence treatment with vandetanib.
Vandetanib at a dose of 300 mg is associated with a substantial and concentration dependent prolongation in QTc (mean 28 msec, median 35 msec). First QTc prolongations occurred most often in the first 3 months of treatment, but continued to first occur after this time. The half-life of vandetanib (19 days) renders this prolongation in QTc interval particularly problematic (see section 4.8). At a dose of 300 mg per day in MTC, ECG QTc prolongation to above 500 msec was observed in a phase III study in 11% of patients. ECG QTc prolongation appears to be dose-dependent. Torsades de pointes and ventricular tachycardia have been uncommonly reported in patients administered vandetanib 300 mg daily. The risk of Torsades may be increased in patients with electrolyte imbalance (see section 4.8).
Vandetanib treatment must not be started in patients whose ECG QTc interval is greater than 480 msec. Vandetanib should not be given to patients who have a history of Torsades de pointes. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
An ECG, and levels of serum potassium, calcium and magnesium and thyroid stimulating hormone (TSH) should be obtained at baseline, at 1, 3, 6 and 12 weeks after starting treatment and every 3 months for at least a year thereafter. This schedule should apply to the period after dose reduction due to QTc prolongation and after dose interruption for more than two weeks. ECGs and blood tests should also be obtained as clinically indicated during this period and afterwards. Frequent ECG monitoring of the QTc interval should be continued.
Serum potassium, serum magnesium and serum calcium should be kept within normal range to reduce the risk of ECG QTc prolongation. Additional monitoring of QTc, electrolytes and renal function are required especially in case of diarrhoea, increase in diarrhoea/dehydration, electrolyte imbalance and/or impaired renal function. If QTc increases markedly but stays below 500 msec, cardiologist advice should be sought.
The administration of vandetanib with substances known to prolong the ECG QTc interval is contraindicated or not recommended (see section 4.3 and 4.5).
The concomitant use of vandetanib with ondansetron is not recommended (see section 4.5)
Patients who develop a single value of a QTc interval of ≥500 msec should stop taking vandetanib. Dosing can be resumed at a reduced dose after return of the QTc interval to pretreatment status has been confirmed and correction of possible electrolyte imbalance has been made.
PRES is a syndrome of subcortical vasogenic oedema diagnosed by a MRI of the brain, has been observed infrequently with vandetanib treatment in combination with chemotherapy. PRES has also been observed in patients receiving vandetanib as monotherapy. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Brain MRI should be performed in any patient presenting with seizures, confusion or altered mental status.
Patients without RET mutation may have a decreased benefit from vandetanib treatment and the benefit/risk balance for this group of patients may therefore differ from that of the group with RET mutations. For patients whose RET mutation status could be negative, a possible lower benefit should be taken into account before individual treatment decisions and the use of vandetanib should be carefully considered because of the treatment related risks. Therefore, RET mutation testing is recommended. When establishing RET mutation status, tissue samples should be obtained if possible at the time of initiation of treatment rather than at the time of diagnosis (see sections 4.1 and 5.1).
Rash and other skin reactions including photosensitivity reactions and palmar-plantar erythrodysaesthesia syndrome have been observed in patients who have received vandetanib.
Mild to moderate skin reactions can be managed by symptomatic treatment, or by dose reduction or interruption. For more severe skin reactions (such as Stevens-Johnson syndrome), referral of the patient to seek urgent medical advice is recommended.
Care should be taken with sun exposure by wearing protective clothing and/or sunscreen due to the potential risk of phototoxicity reactions associated with vandetanib treatment.
Diarrhoea is a disease related symptom as well as a known undesirable effect of vandetanib. Routine anti-diarrhoeal agents are recommended for the treatment of diarrhoea. QTc and serum electrolytes should be monitored more frequently. If severe diarrhoea (CTCAE grade 3-4) develops, vandetanib should be stopped until diarrhoea improves. Upon improvement, treatment should be resumed at a reduced dose (see sections 4.2 and 4.8).
Caution should be used when administering vandetanib to patients with brain metastases, as intracranial haemorrhage has been reported.
Heart failure has been observed in patients who received vandetanib. Temporary or permanent discontinuation of therapy may be necessary in patients with heart failure. It may not be reversible on stopping vandetanib. Some cases have been fatal.
Hypertension, including hypertensive crisis, has been observed in patients treated with vandetanib. Patients should be monitored for hypertension and controlled as appropriate. If high blood pressure cannot be controlled with medical management, vandetanib should not be restarted until the blood pressure is controlled medically. Reduction in dose may be necessary (see section 4.8).
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating vandetanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
Vandetanib is not recommended for use in adult and paediatric patients with moderate or severe renal impairment since there is limited data, and safety and efficacy have not been established (see sections 4.2, 5.1, and 5.2).
Vandetanib is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established. Pharmacokinetic data from volunteers, suggests that no change in starting dose is required in patients with mild, moderate or severe hepatic impairment (see sections 4.2 and 5.2).
Alanine aminotransferase elevations occur commonly in patients treated with vandetanib. The majority of elevations resolve while continuing treatment, others usually resolve after a 1-2 week interruption in therapy. Periodic monitoring of alanine aminotransferase is recommended.
Interstitial Lung Disease (ILD) has been observed in patients receiving vandetanib and some cases have been fatal. If a patient presents with respiratory symptoms such as dyspnoea, cough and fever, vandetanib treatment should be interrupted and prompt investigation initiated. If ILD is confirmed, vandetanib should be permanently discontinued and the patient treated appropriately.
The concomitant use of vandetanib with strong CYP3A4 inducers (such as rifampicin, St John’s Wort, carbamazepine, phenobarbital) should be avoided (see section 4.5).
The benefit of vandetanib in patients with CTN less than 500 pg/ml has not been determined, therefore use in patients with CTN <500 pg/ml should be carefully considered because of the treatment related risks of vandetanib.
All prescribers of Caprelsa must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of Caprelsa therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription.
Paediatric population
Based on height measurements at all visits, all children and adolescents in a paediatric study demonstrated linear growth while receiving vandetanib. However, long term safety data in paediatric patients are not available.
In healthy subjects, the exposure for midazolam (CYP3A4 substrate) was not affected when given together with a single dose of vandetanib at 800 mg.
Vandetanib is an inhibitor of the organic cation 2 (OCT2) transporter. In healthy subjects with wild type for OCT2, the AUC(0-t) and Cmax for metformin (OCT2 substrate) were increased by 74% and 50%, respectively and CLR of metformin was decreased by 52% when given together with vandetanib. Appropriate clinical and/or laboratory monitoring is recommended for patients receiving concomitant metformin and vandetanib, and such patients may require a lower dose of metformin.
In healthy subjects, the AUC(0-t) and Cmax for digoxin (P-gp substrate) were increased by 23% and 29% respectively, when given together due to P-gp inhibition by vandetanib. Furthermore, the bradycardiac effect of digoxin may increase the risk of vandetanib QTc interval prolongation and Torsade de Pointes. Therefore, an appropriate clinical (e.g. ECG) and/or laboratory monitoring is recommended for patients receiving concomitant digoxin and vandetanib, and such patients may require a lower dose of digoxin. (For vandetanib monitoring, see section 4.2 Posology and Method of administration and section 4.4 Special warnings and precautions for use).
As regards other P-gp substrates such as dabigatran, a clinical monitoring is recommended in case of combination with vandetanib.
In healthy subjects, no clinically significant interaction was shown between vandetanib (a single dose of 300mg) and the potent CYP3A4 inhibitor, itraconazole (repeated doses of 200mg once daily). In healthy male subjects, the exposure to vandetanib was reduced by 40% when given together with the potent CYP3A4 inducer, rifampicin. Administration of vandetanib with potent CYP3A4 inducers should be avoided.
In healthy subjects, the Cmax for vandetanib was decreased by 15% while the AUC(0-t) for vandetanib was not affected when given together with omeprazole. Neither the Cmax nor the AUC(0-t) for vandetanib was affected when given together with ranitidine. Therefore, no change in dose of vandetanib is required when vandetanib is given with either omeprazole or ranitidine.
Biliary excretion of unchanged vandetanib is one of the excretion pathways for vandetanib. Vandetanib is not a substrate of multidrug resistance protein 2 (MRP2), p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP).
Vandetanib has been shown to prolong the ECG QTc interval; Torsades de pointes have been uncommonly reported. Therefore, the concomitant use of vandetanib with medicinal products known to also prolong the QTc interval and/or induce Torsades de pointes is either contraindicated or not recommended depending on existing alternative therapies.
If there is no appropriate alternative therapy, not recommended combinations with vandetanib may be made with additional ECG monitoring of the QTc interval, evaluation of electrolytes and further control at onset or worsening of diarrhoea.
Results of a pharmacodynamic and pharmacokinetic interaction study indicated that co-administration with ondansetron in healthy patients appeared to have little effect on the pharmacokinetics of vandetanib, but had a small additive effect on the prolongation of the QTc interval of approximately 10 ms. Therefore, the concomitant use of ondansetron with vandetanib is not recommended. If ondansetron is administered with vandetanib, closer monitoring of serum electrolytes and ECGs and aggressive management of any abnormalities is required.
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation is frequent. In consideration of the high intra-individual variability of the response to anticoagulation, and the possibility of interaction between vitamin K antagonists and chemotherapy, an increased frequency of the INR (International Normalised Ratio) monitoring is recommended, if it is decided to treat the patient with vitamin K antagonists.
Women of childbearing potential must use effective contraception during therapy and for at least four months following the last dose.
There is a limited amount of data on the use of vandetanib during pregnancy. As expected from its pharmacological actions, vandetanib has shown significant effects on all stages of female reproduction in rats (see section 5.3).
If vandetanib is used during pregnancy or if the patient becomes pregnant while receiving vandetanib, she should be apprised of the potential for foetal abnormalities or loss of the pregnancy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus.
There are no data on the use of vandetanib in breast-feeding women. Vandetanib and/or its metabolites is excreted into milk in rats and found in plasma of pups following dosing to lactating rats (see section 5.3).
Breast-feeding is contraindicated while receiving vandetanib therapy.
In rats, vandetanib had no effect on male fertility but impaired female fertility (see section 5.3).
Effects on reproduction in paediatric patients treated with vandetanib are not known.
No studies to establish the effects of vandetanib on ability to drive and use machines have been conducted. However, fatigue and blurred vision have been reported and those patients who experience these symptoms should observe caution when driving or using machines.
The most commonly reported adverse drug reactions have been diarrhoea, rash, nausea, hypertension, and headache.
The following adverse reactions have been identified in clinical studies with patients receiving vandetanib as treatment for MTC. Their frequency is presented in Table 2, adverse reactions using Council for International Organizations of Medical Sciences (CIOMS III), listed by MedDRA System Organ Class (SOC) and at the preferred term level and then by frequency classification. Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from the available data). This section includes only data derived from completed studies where patient exposure is known.
Table 2. Adverse reactions and system organ class:
Very common: Nasopharyngitis bronchitis, upper respiratory tract infections, urinary tract infections
Common: Pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, furuncle, fungal infection, pyelonephritis
Uncommon: Appendicitis, staphylococcal infection, diverticulitis, cellulitis, abdominal wall abscess
Common: Hypothyroidism
Very common: Appetite decreased, Hypocalcaemia
Common: Hypokalaemia, hypercalcaemia, hyperglycemia, dehydration, hyponatremia
Uncommon: Malnutrition
Very common: Insomnia, Depression
Common: Anxiety
Very common: Headache, paraesthesia, dysaesthesia, dizziness
Common: Tremor, lethargy, loss of consciousness, balance disorders, dysgeusia
Uncommon: Convulsion, clonus, brain oedema
Very common: Vision blurred, corneal structural change (including corneal deposits and corneal opacity)
Common: Visual impairment, halo vision, photopsia, glaucoma, conjunctivitis, dry eye, keratopathy
Uncommon: Cataract, accommodation disorders
Very common: Prolongation of ECG QTc interval,*
Uncommon: Heart failure, acute heart failure, rate and rhythm disorders, cardiac conduction disorders, ventricular arrhythmia and cardiac arrest
Very common: Hypertension
Common: Hypertensive crisis, ischaemic cerebrovascular conditions
Not known: Aneurysms and artery dissections
Common: Epistaxis, haemoptysis, pneumonitis
Uncommon: Respiratory failure, pneumonia aspiration
Very common: Abdominal pain, diarrhoea, nausea, vomiting, dyspepsia
Common: Colitis, dry mouth, stomatitis, dysphagia, constipation, gastritis, gastrointestinal haemorrhage
Uncommon: Pancreatitis, peritonitis, ileus, intestinal perforation, faecal incontinence
Common: Cholelithiasis
Very common: Photosensitivity reaction, rash and other skin rections (including acne, dry skin, dermatitis, pruritus), nail disorders
Common: Palmar-plantar erythrodysaesthiesia syndrome, alopecia
Uncommon: Bullous dermatitis
Very common: Proteinuria, nephrolithiasis
Common: Dysuria, hematuria, renal failure, pollakiuria, micturition urgency
Uncommon: Chromaturia, anuria
Very common: Asthenia, fatigue, pain, oedema
Common: Pyrexia
Uncommon: Impaired healing
Very common: ECG QTc interval prolonged
Common: Increase of serum ALT and AST, weight decreased blood creatinine increased
Uncommon: Increased haemoglobin,serum amylase increased
* 13.4% vandetanib patients had QTc (Bazett’s) ≥500 ms compared with 1.0% placebo patients. QTcF prolongation was >20 ms in over 91% of patients, >60 ms in 35%, >100 ms in 1.7%. Eight percent of patients had a dose reduction due to QTc prolongation.
** including two deaths in patients with QTc >550 ms (one due to sepsis and one due to heart failure).
Events such as Torsades de pointes, Stevens-Johnson syndrome, erythema multiforme, interstitial lung disease (sometimes fatal) and PRES (RPLS) have occurred in patients treated with vandetanib monotherapy. It is expected that these would be uncommon adverse reactions in patients receiving vandetanib for MTC.
Ocular events such as blurred vision are common in patients who received vandetanib for MTC. Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated patients; however, routine slit lamp examinations are not required for patients receiving vandetanib.
At various exposure durations, median haemoglobin levels in patients treated with vandetanib were increased by 0.5-1.5 g/dl compared to baseline.
Paediatric clinical trial data with vandetanib in MTC (see section 5.1) obtained during drug development is limited to 16 patients aged 9 years to 17 years with hereditary medullary thyroid carcinoma (Study IRUSZACT0098). Whilst the study size is small owing to the rarity of MTC in children, it is considered representative of the target population. The safety findings in this study are consistent with the safety profile of vandetanib in adult patients with MTC. Long term safety data in paediatric patients are not available.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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